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The Cancer-Testis Gene, MEIOB, Sensitizes Triple-Negative Breast Cancer to PARP1 Inhibitors by Inducing Homologous Recombination Deficiency

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The Cancer-Testis Gene, MEIOB, Sensitizes Triple-Negative Breast Cancer to PARP1 Inhibitors by Inducing Homologous Recombination Deficiency Cancer Biol Med 2021. doi: 10.20892/j.issn.2095-3941.2020.0071 ORIGINAL ARTICLE The cancer-testis gene, MEIOB, sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency Yayun Gu1,2*, Cheng Wang1,2,3*, Rongxuan Zhu4, Jianshui Yang1, Wenwen Yuan1,2, Yanhui Zhu5, Yan Zhou1,2, Na Qin1,2, Hongbing Shen1,2, Hongxia Ma1,2, Hongxia Wang4, Xiaoan Liu5, Zhibin Hu1,2 1State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; 2Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211116, China; 3Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China; 4Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; 5Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China ABSTRACT Objective: The newly defined cancer-testis (CT) gene, MEIOB, was previously found to play key roles in DNA double-strand break (DSB) repair. In this study, we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers (TNBCs). Methods: The Cancer Genome Atlas database was used to quantify the expression of MEIOB. Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC. The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro. Patient-derived xenograft (PDX) models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors. Results: We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors, especially TNBCs. Its activation was significantly associated with poor survival in breast cancer patients [overall, hazard ratio (HR) = 1.90 (1.16–2.06); TNBCs: HR = 7.05 (1.16–41.80)]. In addition, we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells. Further analysis showed that MEIOB participated in DSB repair in TNBCs. However, in contrast to its function in meiosis, it mediated homologous recombination deficiency (HRD) through the activation of polyADP-ribose polymerase (PARP)1 by interacting with YBX1. Furthermore, activated MEIOB was shown to confer sensitivity to PARP inhibitors, which was confirmed in PDX models. Conclusions: MEIOB played an oncogenic role in TNBC through its involvement in HRD. In addition, dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors, so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC. KEYWORDS Cancer-testis gene; MEIOB; triple-negative breast cancer; PARP1 inhibitor; cell proliferation Introduction breast cancer that is negative for the estrogen receptor, pro- gesterone receptor, and human epidermal growth factor Triple-negative breast cancer (TNBC) accounts for approx- receptor 2 (HER2)1. Due to the absence of these three recep- imately 10%–15% of all breast cancers and is defined as tors in TNBC, chemotherapy remains the standard-of-care for TNBC patients both in early and advanced stages2,3. Although chemotherapy can improve the conditions of patients with *These authors contribute equally to this work. early TNBC, the recurrence and metastasis rate of TNBC Correspondence to: Zhibin Hu and Xiaoan Liu 4-6 E-mail: [email protected] and [email protected] patients is high for patients with advanced disease . Thus, ORCID ID: https://orcid.org/0000-0002-8277-5234 and novel targeted approaches are urgently needed for the treat- https://orcid.org/0000-0001-5716-0740 ment of TNBC. Recently, olaparib, a polyADP-ribose poly- Received February 18, 2020; accepted July 08, 2020. merase (PARP) inhibitor, was approved by the US Food and Available at www.cancerbiomed.org ©2021 Cancer Biology & Medicine. Creative Commons Drug Administration for the treatment of breast cancers Attribution-NonCommercial 4.0 International License with BRCA1/2 mutations7. BRCA1/2 mutations in cancers Cancer Biol Med Vol 18, No 1 February 2021 75 are prototypic molecular alterations that confer homologous Cell culture and cell line authentication recombination deficiency (HRD) and sensitivity to DNA dam- aging therapy8,9. In addition, some studies show that cancers MDA-MB-231 and MDA-MB-468 cells were obtained from with genetic deficiencies involved in homologous recombina- the American Type Culture Collection (Manassas, VA, USA), tion repair other than BRCA mutations, such as deficiencies and the SUM1315MO2 cell line was provided by Stephen in ATM, ATR, PALB2, and FANC, are also highly susceptible Ethier (University of Michigan), as previously described21. to PARP inhibitor treatment10,11. A group of cancer-testis The cells were cultured in Dulbecco’s Minimal Eagle’s Medium (CT) genes is essential for homologous recombination12,13. (DMEM) (Gibco, Gaithersburg, MD, USA) containing 10% These genes include the meiotic topoisomerase that catalyzes fetal bovine serum (FBS; Gibco) and incubated at 37 °C in 5% 14 DNA double-strand breaks , components of the synaptone- CO2 and saturated humidity. The transient overexpression or mal complex (SYCP1)15,16, and multiple proteins that mediate knockdown of MEIOB was performed using siRNA or MEIOB homologue alignment or recombination (MEIOB)17,18. Luo plasmids. The 3 cell lines were cultured in low glucose DMEM. et al.17 revealed that MEIOB is involved in highly ordered DNA All cell lines were cultured at 37 °C in a humidified cham- doubled-strand break (DSB) repair during meiotic homolo- ber with 5% CO2, tested negative for mycoplasma (Lonza, gous recombination, by forming a complex with its cofactor, Rockville, MD, USA), and were authenticated using short tan- SPATA22. In our previous study, we identified MEIOB as a dem repeat profiling within the last 3 years (FuHeng Biology, new CT gene involved in the carcinogenesis of lung cancer19. Xian, China). Nevertheless, its role and precise mechanism in TNBC remain unknown. We therefore characterized the involvement of RNA isolation and qRT-PCR MEIOB in the DNA repair process in TNBC patients, and fur- ther examined whether dysregulated MEIOB in TNBC con- Total RNA was extracted using TRIzol reagent (Thermo Fisher ferred sensitivity to PARP inhibitors. Scientific, Waltham, MA, USA) and reverse transcribed using the PrimeScript RT Reagent Kit (Takara, Mountain View, CA, Materials and methods USA). Expression of cDNA was quantified using the TaqMan Gene Expression Master Mix (Thermo Fisher Scientific) with Patient data an ABI 7900HT System (Applied Biosystems, Foster City, CA, USA). Primer sequences and their respective amplicon sizes We determined the expression of MEIOB in breast cancer for RT-PCR are summarized in Supplementary Table S1. tissues by reanalyzing the raw RNA sequencing data of 1,058 patients from The Cancer Genome Atlas (TCGA) datasets. A Western blot analysis standard STAR-HTSeq-DESeq2 pipeline was used to quantify gene expression20. We used normalized read counts > 5 as the The cells were washed 3 times with phosphate-buffered saline cutoff to define the expression of MEIOB. The clinical infor- (PBS), and the total protein was isolated using protein lysis mation was obtained from Firehose Broad GDAC (http://gdac. buffer. After centrifugation at 12,000 × g for 15 min at 4 °C, broadinstitute.org/, version 2016_01_28). To define signature the cell debris was removed, and the supernatant (cell lysate) 3, we converted all mutation data from WGS datasets into a was used for Western blot. Protein concentrations were meas- matrix (M) composed of 96 features comprising mutation ured using a BCA assay (Beyotime, Beijing, China). Equal counts for each mutation type (C>A, C>G, C>T, T>A, T>C, amounts of protein were separated by 10% SDS-PAGE and and T>G) using each possible 5′ and 3′ context for all sam- then transferred to polyvinylidene difluoride membranes ples, and applied the R package deconstructSigs12 to deter- (Millipore, Billerica, MA, USA). The membranes were blocked mine the proportion of each known mutational signature. The in blocking buffer (Tris-buffered saline, pH 7.6, 5% skim milk, tissue array used in immunohistochemistry (IHC) analysis was and 0.05% Tween) at room temperature for 1.5 h. Then, the obtained from Shanghai Outdo Biotech, Shanghai, China. This membranes were incubated at 4 °C overnight with primary study was approved by the ethics committee of Nanjing Medical antibody diluted in blocking buffer, followed by incubation University (Approval No. 2015-SRFA-112), and all patients with the corresponding secondary anti-IgG horseradish per- completed the Clinical Sample Informed Consent Form. oxidase conjugate (Santa Cruz Biotechnology, Santa Cruz, 76 Gu et al. MEIOB sensitizes TNBC to PARP1 inhibitors CA, USA) for 1.5 h. The antibody binding was visualized 3–5 min and counted (9 random fields) by 2 independent inves- with ECL solution (Pierce Biotechnology, Rockford, IL, USA). tigators. The results were normalized to those of the controls. The expression of proteins was assessed by immunoblotting and was normalized to that of glyceraldehyde 3-phosphate Cell cycle analysis of tumor cells dehydrogenase (GAPDH). The antibodies were as follows: anti-GAPDH (KC-5G4; Kang Chen Tech, Shanghai, China), The cell cycle was analyzed by flow cytometry. For cell cycle anti-MEIOB (ab178756; Abcam, Cambridge, MA, USA), anti- analysis, transfected lung cancer cells were suspended in 75% green fluorescent protein (GFP; 66002-I-Ig; Proteintech, ethanol overnight and centrifuged at 1,000 rpm. The cell pel- Wuhan, China), anti-RAD51 (ab63801; Abcam), anti- lets were washed twice with PBS and re-suspended in PBS con- YBX1 (ab76149; Abcam), anti-PARP1 (sc-8007; Santa Cruz taining 50 mg/mL propidium iodide and 100 g/mL DNase-free Biotechnology), and anti-PAR (ALX-804-220-R100; Enzo Life RNase A. The cell suspension was incubated for 30 min at 37 °C Sciences, Farmingdale, NY, USA).
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